Pronounced neurogenic vasodilation, mediated by non-sympathetic neural outflow from the central nervous system, occurs in both the cerebral and extracerebral cephalic circulation in a number of species. In the cat, acetylcholine and vasoactive intestinal polypeptide (VIP) havve been strongly implicated as transmitters in these neurodilating systems. However, the specific origins and distribution of nerves which contain acetylcholine and VIP have been determined only to a limited extent. Likely pre- and post-synaptic interactions between the cholinergic and VIPergic neural outflow at sites where these systems overlap, and the mechanisms whereby they cause their effects, have not been elucidated. A spectrum of neurogenic vasodilator behavior, ranging from fully atropine-sensitive to completely atropine-resistant, exists in different cephalic blood vessels taken from the cat, rat, and rabbit. In this proposal, arteries from these species have been selected to permit, by comparison of their dilator characteristics, separation of the roles and interactions of acetylcholine and VIP. The specific aims of this study include: (1) a detailed study of the origin and distribution of cholinergic and VIPergic perivascular nerves in the cephalic circulation of the rat and a comparison of these findings with previous observations in the cat, (2) an evaluation of presynaptic interactions between acetylcholine and VIP which may influence their release from perivascular nerves in the cat and rabbit, and (3) measurement of the vascular smooth muscle cell electrophysiological correlates of neurogenic vasodilation. The following techniques will be employed: (1) measurements of choline acetyltransferase activity, (2) immunohistochemical observation of VIP-containing perivascular nerves and cells, (3) determinations of VIP content and release from arterial samples using a radioimmunoassay for VIP, (4) estimates of acetylcholine release following tissue loading with a labeled precursor, and (5) intracellular recording of vascular smooth muscle membrane potential using microelectrodes. These studies will provide a matrix of new information about the mechanisms of neurogenic vasodilation, help clarify the functional significance of a type of innervation which involves two dilator transmitters, and contribute to an understanding of the neural regulation of tone under normal conditions in vascular beds which are involved in such pathological conditions as cerebal infarction and ischemia and vascular headache; this in turn, could lead to new strategies for pharmacological management of such diseases.